DOI: 10.1002/chem.201304164
Communication
& Synthetic Methods
On the Frontier Between Nucleophilic Aromatic Substitution and Catalysis Martin Pichette Drapeau,[a, b] Thierry Ollevier,*[a] and Marc Taillefer*[b] Abstract: A study on the arylation of heteroatom nucleophiles by using activated haloarenes, with or without metal catalysts, is reported. A discussion concerning the involvement of traces of metals is presented, supported by an unexpected ''ligand'' effect in the absence of added metal catalysts. We believe that the frontier between nucleophilic aromatic substitution and catalysis will likely prove to be much harder to delimit than is generally thought.
Nucleophilic aromatic substitution (SNAr) reactions of aryl halides, allowing for the formation of C(aryl) heteroatom bonds, have been known since the 19th century.[1] Depending on the reaction conditions, several mechanisms can be considered for this transformation. The most important of these mechanisms is classical addition–elimination (SNAr mechanism), in which halogens ortho or para to strong electron-withdrawing groups are substituted by heteroatom nucleophiles through Meisenheimer–Jackson complexes.[2] There is an abundance of literature reports on the reactions of O- and N-nucleophiles with aryl halides (F, Cl, or Br), activated by electron-withdrawing groups, that require classical or microwave heating, or sonochemical conditions.[3] In particular, the nitro functionality acts as a highly activating group in SNAr because of its excellent ability to stabilize reaction intermediates through resonance structures. Another widely used method for C(aryl) heteroatom bond formation requires the presence of transition-metal catalysts for the coupling of nucleophiles with non-activated and activated aryl halides.[4] Thus, electron-deficient aryl iodides, bromides, chlorides, and even fluorides have been used in various metal-catalyzed protocols. However, the latter two reagents in particular are excellent substrates for SNAr reac-
tions. From a purely theoretical point of view, one could question the necessity of added metals in some of the corresponding systems. In the same manner, even for activated aryl iodides, which are among the worst substrates for SNAr reactions, some rare examples of coupling with nucleophiles in metal-free conditions have been reported. These examples make use of highly activated 1-iodo-4-nitrobenzene, under either microwave/sonochemical[5] or thermal conditions,[6] as well as 4-iodobenzonitrile and 4-iodoacetophenone, as reported previously by our group.[6b] Herein, we wish to disclose our study on reactions of electron-deficient aryl halides with aromatic heteroatom (O- and N-) nucleophiles, from which unexpected results were obtained. Taking into account the few previous literature reports on SNAr reactions of phenols with 1-iodo-4-nitrobenzene,[6] the reaction of the latter with 3,5-dimethylphenol was first revisited. Indeed, nucleophilic aromatic substitution involving electronpoor aryl iodides, even when substituted by the strongly activating NO2 group, is not really expected. In our first test, which was a control experiment in the absence of a base, no reaction occurred at 90 8C in DMF, a classical solvent for SNAr (Table 1, entry 1). However, under these conditions, the desired diaryl ether 1 was quantitatively formed
[a] M. Pichette Drapeau, Prof. Dr. T. Ollevier Dpartement de Chimie Pavillon Alexandre-Vachon, Universit Laval 1045, avenue de la Mdecine, Qubec (Qc), G1V 0A6 (Canada) E-mail: [email protected] [b] M. Pichette Drapeau, Dr. M. Taillefer CNRS, UMR 5253, AM2N Institut Charles Gerhardt Montpellier ENSCM 8, rue de l’cole Normale, F-34296 Montpellier Cedex 5 (France) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304164 and includes general procedures for isolation and full characterization of every product, as well as optimization tables. Chem. Eur. J. 2014, 20, 5231 – 5236
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Table 1. Reaction of 3,5-dimethylphenol with 1-iodo-4-nitrobenzene.[a]
1 2 3 4 5 6 7 8 9 10 11 12
Base (purity %)[b]
Solvent
Yield 1 [%][c]
Absence Cs2CO3 (99.995) K3PO4 (97) K2CO3 (97) LiOtBu (99.9) LiOH (99.995) NaOH (99.99) CsOH (99.95) Pyridine (98) Cs2CO3 (99.995) Cs2CO3 (99.995) Cs2CO3 (99.995)
DMF DMF DMF DMF DMF DMF DMF DMF DMF toluene MeCN DMSO
0 100[d,e] 99 68 55 93 76 83 0 0 30 85
[a] Conditions: 3,5-Dimethylphenol (1.0 equiv), 1-iodo-4-nitrobenzene (1.5 equiv), base (2.5 equiv), solvent (0.25 m). [b] As determined by the supplier. [c] Yield calculated by 1H NMR spectroscopy by using 1,3,5-trimethoxybenzene as an internal standard. [d] 98 % isolated yield. [e] 61 % yield was calculated by using an equimolar ratio of phenol and aryl iodide.
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Communication by the addition of Cs2CO3 ; changing the base to K3PO4 also gave an almost complete conversion (Table 1, entries 2 and 3).[7] On the other hand, using K2CO3 led to a good yield and LiOtBu gave only fair results (Table 1, entries 4 and 5). Hydroxide bases were then tested, LiOH resulted in a better conversion than that of both NaOH and CsOH (Table 1, entry 6 versus entries 7 and 8).[8] No reaction occurred when an organic base (pyridine) was used or when the reaction was conducted in toluene, the starting material being quantitatively recovered in both cases (Table 1, entries 9 and 10). A low yield was obtained when the reaction was performed in acetonitrile under reflux, whereas on changing the solvent to DMSO a good yield was achieved (Table 1, entries 11 and 12). Cs2CO3 was chosen for further exemplification studies to allow a comparison of our results with those in the literature. Indeed, Cs2CO3 (in association with DMF) is very frequently used in related metal-catalyzed C O coupling reactions. Although these results seem to confirm preliminary reports on SNAr reactions of 1-iodo-4-nitrobenzene,[6] we controlled the purity of the reagents to detect the possibility of catalysis by trace metal contaminants.[9] Cs2CO3 was purchased from Sigma–Aldrich (99.995 % trace metals basis) and Alfa Aesar (99.994 % trace metals basis). For the latter, a certificate of analysis was available and indicated that metals known to catalyze such reactions (mainly palladium, copper, and rhodium) were not detected in measurable amounts by inductively coupled plasma (ICP) analysis.[10] In addition, both reaction partners (3,5-dimethylphenol and 1-iodo-4-nitrobenzene) were carefully purified by column chromatography, and reactions were conducted in new glassware by using magnetic stirrers treated with aqua regia (nitro-hydrochloric acid) prior to use. Even with these precautions, the reactivity remained essentially the same for each individual reaction. Next, we attempted to extend the scope of this method to various phenols and activated aryl iodides. It is noteworthy that except one previous report,[6b] aryl iodides with a substituent other than NO2 have never been used in SNAr reactions. For each type of substituted aryl iodide, a comparison of its reactivity with the corresponding bromide and chloride was also undertaken to verify the expected order of reactivity of aryl halides; I < Br Cl according to the literature. Because of the high reactivity of nitro-substituted aryl halides, reactions of these substrates were carried out at room temperature. We first observed that the reaction of 1-iodo-4-nitrobenzene with 3,5-dimethylphenol proceeded to completion at room temperature, although the reaction time was very long (Table 2, entry 1). As previously observed, increasing the temperature to 90 8C greatly reduced the required reaction time (Table 2, entry 1’). Reactions of 3,5-dimethylphenol with 1-bromo-, 1-chloro-, and 1-fluoro-4-nitrobenzene also furnished 1 in excellent yields at room temperature and in acceptable reaction times for 1-chloro, and 1-fluoro-4-nitrobenzene (Table 2, entries 2–4). Furthermore, the order of reactivity of the four aryl halides is in good agreement with the literature for SNAr reactions. The reactions of phenol and 4-fluorophenol with 1-iodo4-nitrobenzene under similar conditions also provided diaryl ethers 2 and 3 (Table 2, entries 5 and 6) in quantitative yields. Chem. Eur. J. 2014, 20, 5231 – 5236
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For these two entries, conducting the reactions at 90 8C also greatly reduced the required reaction times (Table 2, entries 5’ and 6’). On using 1-iodo-2-nitrobenzene, a satisfying yield of 4 was obtained at 90 8C (Table 2, entry 7).[11] Importantly, no trace of the desired product was detected on reaction of 1-iodo-3nitrobenzene with 3,5-dimethylphenol at this temperature, demonstrating that an appropriate substitution pattern (ortho and para versus meta), typical of addition–elimination SNAr reactions of aryl halides, is crucial for the reaction to proceed. In addition, aryl halides substituted by the cyano group were also tested. The reactions of 3,5-dimethylphenol with 4-iodo-, 4-bromo-, and 4-chlorobenzonitrile furnished diaryl ether 5 in good yields at 120 8C (Table 2, entries 8–10). The difference in reactivity between the aryl halides was clearly highlighted when the temperature was lowered to 90 8C; 4-iodobenzonitrile gave a significantly lower conversion than 4-bromo- and 4-chlorobenzonitrile (Table 2, entries 8’–10’). Phenols substituted by various electron-withdrawing and electrondonating groups could be coupled with 4-iodobenzonitrile to give diaryl ethers 6–9 in yields ranging from 53 to 97 %, demonstrating the generality of this method (Table 3, entries 11– 14). Moreover, when 2-iodobenzonitrile was used, an excellent 97 % yield of diaryl ether 10 was obtained (Table 2, entry 15). The reactions of 4-haloacetophenones with 3,5-dimethylphenol were also investigated. It was observed that an elevated temperature (145 8C) is necessary to furnish the desired diaryl ether 11 in moderate to excellent yields (Table 2, entries 16– 18). When the reactions were repeated, at 120 8C, with the three aryl halides, the best conversion was obtained in the case of 4-bromoacetophenone, whereas 4-iodo- and 4-chloroacetophenone gave modest results (Table 2, entries 16’–18’). The trifluoromethyl group, a weak electron-withdrawing group, was also tested. The reactions of 4-halobenzotrifluorides with 3,5-dimethylphenol gave the corresponding product 12 in yields ranging from 60 to 91 % at a surprisingly “low” temperature (145 8C), despite the weak activation from the trifluoromethyl group (Table 2, entries 19–21). Even more surprising was the fact that the relative reactivity of the aryl halides decreased in the order I Br > Cl,[12] which is not in perfect agreement with the literature.[1, 13] Moreover, the tendency was the same when the reactions were conducted at 120 8C (Table 2, entries 19’–21’). Finally, a 65 % yield of diaryl ether 13 was obtained by the reaction of 3,5-dimethylphenol with 2-iodobenzotrifluoride (Table 2, entry 22). It is noteworthy that we never observed reduction products of the aryl iodides under these conditions, with the exception of the reaction using 1-iodo-2nitrobenzene. This methodology was next extended to nitrogen nucleophiles (Table 3). We tested the reactivity of azoles, with pyrazole being chosen as the model substrate. The reaction of pyrazole with 1-iodo-4-nitrobenzene at 120 8C provided N-aryl azole 14 in excellent yield (Table 3, entry 1). It was also possible to generate product 15 in very good yields from the corresponding 4-halobenzonitriles at 145 8C (Table 3, entries 2–4), and product 16 in fair to good yields by using 4-halobenzotrifluorides (Table 3, entries 5–7). For the latter, 4-chlorobenzotrifluoride again proved to be less reactive than its iodo- and
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Communication Table 2. Synthesis of diaryl ethers 1–13.[a]
R1
X, R2
Diaryl ether
T [oC], t [h]
Yield [%][b]
22, 240 90, 18 22, 80 22, 40 22, 6
95 100 96 98 99
1 1’ 2 3 4
m, m’ (CH3)2
5 5’
H
I, p-NO2
22, 240 90, 18
97 (95) 98
6 6’
p-F
I, p-NO2
22, 240 90, 18
98 (96) 99
7
m, m’ (CH3)2
I, o-NO2
90, 18
62 (60)
120, 24 90, 24 120, 24 90, 24 120, 24 90, 24
83 (76) 50 81 (75) 93 80 (72) 85
I, p-NO2 Br, p-NO2 Cl, p-NO2 F, p-NO2
(93) (98) (92) (96) (98)
8 8’ 9 9’ 10 10’
m, m’ (CH3)2
11
H
I, p-CN
120, 24
84 (81)
12
p-F
I, p-CN
120, 24
95 (92)
13
p-OMe
I, p-CN
120, 24
97 (93)
14
m, m’ (CF3)2
I, p-CN
120, 24
53 (46)
15
m, m’ (CH3)2
I, o-CN
120, 24
97 (94)
145, 120, 145, 120, 145, 120,
24 24 24 24 24 24
62 (49) 45 90 (71) 75 95 (73) 64
145, 120, 145, 120, 145, 120,
24 24 24 24 24 24
91 (70) 50 83 (64) 45 60 (40) 18
16 16’ 17 17’ 18 18’
I, p-CN Br, p-CN Cl, p-CN
I, p-COMe m, m’ (CH3)2
Br, p-COMe Cl, p-COMe
19 19’ 20 20’ 21 21’
m, m’ (CH3)2
22
m, m’ (CH3)2
I, p-CF3 Br, p-CF3 Cl, p-CF3
I, o-CF3
reflux, 24
83 (65)
[a] Conditions: Phenol (1.0 equiv), aryl halide (1.5 equiv), Cs2CO3 (2.5 equiv), DMF (0.25 m). [b] Yield calculated by 1H NMR spectroscopy by using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are given in parentheses.
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bromo- counterparts, as already observed for the reactions of these substrates with phenols. Conducting the reaction of imidazole or pyrrole with 1-iodo-4nitrobenzene resulted in no conversion of the nucleophile, suggesting that an a-effect[14] is critical for the success of the coupling of azoles with aryl halides (Table 3, entry 8). Indeed, the reaction between 1,2,4-triazole and 1-iodo-4-nitrobenzene furnished N-aryl azole 17 in very good yield (Table 3, entry 9). In the literature, the arylation of phenols or nitrogen heterocycles involving electron-deficient iodo-, bromo-, and sometimes chloroarenes is described, at comparable or lower temperatures than those in our study, by means of transition-metal-catalyzed protocols (mainly involving copper and palladium species). However, the need for a catalyst, or the reaction temperature at which the use of a catalyst is required, is not always evident because the control experiments in the absence of metals are often missing or only concern the simplest category of substrates (halobenzenes). For example, concerning the C O bond formation in the case of halonitroarenes, it is clear from this study (Table 2) that the use of a metal catalyst will rarely be necessary. Indeed, even for iodoarenes, which are among the worst substrates for SNAr reactions, good to excellent yields of diarylethers 1–4 were obtained at a reasonable temperature and reaction time (90 8C, 18 h: Table 2, entries 1’, 5’, 6’, and 7). With the less-activating cyano substituent, the same conclusion may be drawn for the arylation at 90 8C, in the absence of a catalyst, of 3,5-dimethylphenol with bromoand chloroarenes (Table 2, entries 9’ and 10’). As expected, a higher temperature (120 8C) was necessary for the ar-
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication system at this temperature and noticed quantitative coupling between 3,5-dimethylphenol and 4iodoacetophenone (CuI 10 mol %/ TMHD 20 mol %). Importantly, we [b] Azole X, R N-aryl azole T [8C] Yield [%] observed an unexpected effect in the control experiments we per[c] 1 pyrazole I, p-NO2 120 98 (95) formed during this study. Indeed, in the presence of the b-diketone 2 I, p-CN 145 88 (85) 3 Br, p-CN 145 92 (86) pyrazole (TMHD), without copper,[17] the 4 Cl, p-CN 145 93 (90) conversion of 3,5-dimethylphenol into diaryl ether 11 was increased 5 I, p-CF3 145 84 (75) from 45 to 65 and 92 % with 0, 6 Br, p-CF3 145 81 (72) pyrazole 0.2, and 2 equivalents of TMHD, 145 59 (43) 7 Cl, p-CF3 respectively, in otherwise un145 0 8 imidazole I, p-NO2 changed conditions (Table 4, entries 1–3). For 4-bromoacetophe[c] 120 86 (83) 9 1,2,4-triazole I, p-NO2 none, a similar enhancement of conversion into diaryl ether 11 [a] Conditions: Azole (1.0 equiv), aryl iodide (1.5 equiv), Cs2CO3 (2.5 equiv), DMF (0.25 m). [b] Yield calculated by 1 was observed. Addition of only H NMR spectroscopy by using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are given in pa0.2 equivalents of TMHD inrentheses. [c] 18 h. creased the conversion from 75 to 100 % (Table 4, entries 4 and 5). On the contrary, addition of 0.2 equivalents of TMHD did ylation, in excellent yields, of various phenols with iodobenzonot have any effect on the coupling reaction of 4-chloroacetonitriles (Table 2, entries 8, 11–15). However, if the use of phenone (Table 4, entries 6 and 7). a metal catalyst is not necessary in these cases, it is essential Concerning substrates with a trifluoromethyl substituent, when working at lower temperatures. For example, no trace of the yields of coupling products are good when the reaction is diaryl ether 5 was obtained by reacting 3,5-dimethylphenol carried out at 145 8C, but disappointing at 120 8C (Table 2, enwith 4-iodobenzonitrile at 50 8C (compared with 83 % yield at tries 19–21’). Noticeably, no similar positive effect was ob120 8C).[15] On the other hand, conducting the reaction at 50 8C served when the b-diketone alone was added to the reaction in the presence of CuI (0.5 mol %) and 2,2,6,6-tetramethylhepof 3,5-dimethylphenol and 4-iodobenzotrifluoride at these eletanedione (1 mol %, TMHD) provided a very low (5 %) yield of vated temperatures. the desired diaryl ether, 5, (Scheme 1).[16] With a higher loading On the basis of our general results, one could consider, in of the copper catalyst (10 mol %) and ligand (20 mol %), a quansome cases, that trace metals are involved in the reactions pretitative yield was obtained. sented in this article.[9] For the C O bond formation (Table 2), this suggestion would provide an explanation for the reaction of 3,5-dimethylphenol with 4-iodobenzotrifluoride invariably proceeding with better conversion (and yield) than the reaction of 3,5-dimethylphenol with 4chlorobenzotrifluoride (Table 2, Scheme 1. Reaction of 3,5-dimethylphenol with 4-iodobenzonitrile: A comparative study. Conditions: 3,5-Dimecompare entries 19 and 19’ with thylphenol (1.0 equiv), 4-iodobenzonitrile (1.5 equiv), Cs2CO3 (2.5 equiv), DMF (0.25 m). 21 and 21’); iodine is a better leaving group in metal-catalyzed Thus, two mechanistic pathways seemingly compete. The coupling reactions. Indeed, one could imagine that catalysis choice of metal-catalyzed or SNAr conditions depends on the plays a more important role than SNAr when the electron-withtemperature threshold tolerated by the substituents and on drawing group is not sufficiently strong (CF3 or MeCO versus the eventual interest to avoid metal traces, for example in the NO2, for example). For the C N bond formation (Table 3), the synthesis of molecules of pharmaceutical interest. same hypothesis can be proposed for the reactions of pyraWith the acetyl substituent, the presence of a catalyst is not zoles at 145 8C; 4-iodobenzotrifluoride reacts more smoothly necessary at 145 8C (Table 2, entries 16–18). At 120 8C, the yield than 4-chlorobenzotrifluoride (Table 3, entries 5 and 7). For the of coupling product is particularly low for the iodo derivative results presented in Table 4, a similar argument could be ap(Table 2, entry 16’). We tested a classical copper catalytic plied. Thus, in reactions of iodo- and bromo-substituted acetoTable 3. Synthesis of N-aryl azoles 14–17.[a]
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Communication Table 4. The effect of the addition of 2,2,6,6-tetramethylheptanedione on the arylation of 3,5-dimethylphenol with 4-haloacetophenones without added copper catalysts.[a]
1 2 3 4 5 6 7
X
TMHD [equiv]
Conversion to 11 [%][b]
I I I Br Br Cl Cl
– 0.2 2 – 0.2 – 0.2
45 65[c] 92 75 100 65 64
[a] Conditions: 3,5-Dimethylphenol (1.0 equiv), 4-haloacetophenone (1.5 equiv), Cs2CO3 (2.5 equiv), DMF (0.25 m). [b] 1H NMR conversion based on phenol by using 1,3,5-trimethoxybenzene as an internal standard. [c] Quantitative yield achieved by adding 10 mol % of CuI.
phenones, the addition of the b-diketone could enhance the reactivity of transition metals that may already be present in the reaction mixture. The fact that the reactivity of 4-chloroacetophenone was unchanged by the addition of a ligand suggests that, in this case, nucleophilic aromatic substitution alone explains phenol arylation. Such an effect has been disclosed for copper-catalyzed arylation of nucleophiles with iodoarenes by using N,N’-dimethylethylenediamine (DMEDA).[18] The presence of the diamine ligand is thought to increase the potency of the catalyst, which is present in part-per-million loadings. Interestingly, the ligand-to-metal ratio needs to be very high, otherwise no coupling takes place. In our case, the use of DMEDA did not provide any enhancement to the reactions described in Table 4. Trace amounts of transition metals, which could have an effect on the reaction outcome when the b-diketone is added, may ultimately be provided by any of the reagents used in the arylations. However, the presence of trace metals would be rather surprising, considering that the phenols, aryl halides, 2,2,6,6-tetramethylheptanedione, and DMF were extensively purified before the reactions, and cesium carbonate was obtained in the highest purity (99.995 %) commercially available. Moreover, some of our results do not support the intervention of metal catalysis. For example, the absence of any “ligand” effect (without copper) on the coupling of 4-iodobenzotrifluoride is not in accordance with this hypothesis. The same applies for the coupling of 3,5-dimethylphenol with 4-iodoacetophenone in the presence of 20 mol % of TMHD. In this case, a 65 % yield of coupling product is obtained, whereas a quantitative yield is obtained by using 4-bromoacetophenone (Table 4, entries 2 and 7). Metal catalysis should arguably favor the reaction of the iodoarene, or at least give comparable yields to the reaction of the bromoarene. However, it seems unlikely that the b-diketone can alone promote coupling reactions between phenols and aryl halides. It is worth noting that these reactions could eventually proceed via aryne intermediates (benzyne mechanism); however, Chem. Eur. J. 2014, 20, 5231 – 5236
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strong bases are traditionally required for this type of SNAr reaction, generally providing a mixture of regioisomers. However, we never experienced selectivity problems, even at elevated temperatures.[19] Concerning the possibility of free-radical SNAr mechanisms (SRN1), radical scavengers 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO), galvinoxyl, and acrylonitrile failed to inhibit the reactions shown in Table 2, suggesting that radicals are not involved. In summary, we have reported conditions for reactions of aromatic heteroatom nucleophiles with electron-deficient aryl halides without the need for added transition-metal salts. It appears from this study that before using metal catalysts, control experiments in the absence of metal catalysts are necessary for every activated aryl halide, including iodides. Incidentally, these control experiments are often missing in the literature or concern the simplest category of substrates (halobenzenes). The choice between SNAr and catalysis would then depend on the temperature threshold tolerated by the substrates and on the eventual interest to avoid metal traces, for example in the synthesis of molecules of pharmaceutical interest. We do not have clear hypotheses for the possible reaction pathways. With regard to the great care with which we undertook this study, it would seem unwise to affirm that the reactions of activated iodo- and bromoarenes described herein are catalyzed by trace amounts of transition metals. However, some results, which include the unexpected “ligand” effect observed for the arylation of 3,5-dimethylphenol with 4-iodo and 4-bromoacetophenone, support this theory. Theoretically determining the frontier between nucleophilic aromatic substitution and catalysis will likely prove to be much harder than is generally thought.
Acknowledgements This work was financially supported by Natural Sciences and Engineering Research Council of Canada (NSERC), Fonds de recherche du Qubec–Nature et Technologies (FRQNT), Conseil Franco-Qubcois de Coopration Universitaire (CFQCU), Centre in Green Chemistry and Catalysis (CGCC), Universit Laval, Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche (ANR), and Ecole Nationale Suprieure de Chimie de Montpellier (ENSCM). M.P.D. thanks FRQNT for a doctoral scholarship and an international internship grant, as well as CGCC for a complementary doctoral scholarship. Keywords: aryl halides · catalysis · diaryl ether · nucleophilic aromatic substitution · transition metals
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[1] a) J. F. Bunnett, R. E. Zahler, Chem. Rev. 1951, 49, 273; b) J. March, M. B. Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Sixth Edition, Wiley-Interscience, Hoboken, 2007, p. 853. [2] a) C. L. Jackson, F. H. Gazzolo, Am. Chem. J. 1900, 23, 376;b) J. Meisenheimer, Justus Liebigs Ann. Chem. 1902, 323, 205; c) C. L. Jackson, R. B. Earle, Am. Chem. J. 1903, 29, 89. [3] For a representative sample, see: a) M. J. Rarick, R. Q. Brewster, F. B. Dains, J. Am. Chem. Soc. 1933, 55, 1289; b) S. D. Ross, J. Am. Chem. Soc. 1959, 81, 2113; c) H. Bader, A. R. Hansen, F. J. McCarty, J. Org. Chem. 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[7] [8] [9]
1966, 31, 2319; d) F. Pietra, F. Del Cima, J. Chem. Soc. Perkin Trans. 2 1972, 1420; e) M. L. Cerrada, J. Elguero, J. de La Fuente, C. Pardo, M. Ramos, Synth. Commun. 1993, 23, 1947; f) M. Kidwai, P. Sapra, B. Dave, Synth. Commun. 2000, 30, 4479; g) R. Gujadhur, D. Venkataraman, Synth. Commun. 2001, 31, 2865; h) P. Magdolen, M. Meciarova, S. Toma, Tetrahedron 2001, 57, 4781; i) W. Li, L. Yun, H. Wang, Synth. Commun. 2002, 32, 2657; j) P. Wipf, S. M. Lynch, Org. Lett. 2003, 5, 1155; k) F. Li, Q. Wang, Z. Ding, F. Tao, Org. Lett. 2003, 5, 2169; l) Z.-B. Xu, Y. Lu, Z.-R. Guo, Synlett 2003, 564; m) S. V. Ankala, G. Fenteany, Synlett 2003, 825; n) G. L. Rebeiro, B. M. Khadilkar, Synth. Commun. 2003, 33, 1405; o) H. Xu, F. Ye, H.-L. Dai, Chin. J. Chem. 2008, 26, 1465. For reviews on copper as catalyst (modified Ullmann condensation), see: a) S. Ley, A. W. Thomas, Angew. Chem. 2003, 115, 5558; Angew. Chem. Int. Ed. 2003, 42, 5400; b) F. Monnier, M. Taillefer, Angew. Chem. 2009, 121, 7088; Angew. Chem. Int. Ed. 2009, 48, 6954; For reviews on palladium species as catalysts (Buchwald – Hartwig reaction), see: c) J. F. Hartwig, Angew. Chem. 1998, 110, 2154; Angew. Chem. Int. Ed. 1998, 37, 2046; d) B. Schlummer, U. Scholz, Adv. Synth. Catal. 2004, 346, 1599; e) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27; For a combined review on copper and palladium species as catalysts under aqueous conditions, see: f) M. Carril, R. SanMartin, E. Domnguez, Chem. Soc. Rev. 2008, 37, 639. For SNAr reactions of activated aryl iodides under forcing conditions, see: a) T. Fuchigami, T. Awata, T. Nonaka, M. M. Baizer, Bull. Chem. Soc. Jpn. 1986, 59, 2873; b) T. Ibata, Y. Isogami, J. Toyoda, Chem. Lett. 1987, 1187; c) T. Ibata, Y. Isogami, J. Toyoda, Bull. Chem. Soc. Jpn. 1991, 64, 42; d) M. Mecˇiarov, J. Podlesna, S. Toma, Monatsh. Chem. 2004, 135, 419. For the only reported SNAr reactions of activated aryl iodides under thermal heating conditions, see: a) J. S. Sawyer, E. A. Schmittling, J. A. Palkowitz, W. J. Smith, III, J. Org. Chem. 1998, 63, 6338; b) N. Xia, M. Taillefer, Chem. Eur. J. 2008, 14, 6037; c) A. B. Naidu, E. A. Jaseer, G. Sekar, J. Org. Chem. 2009, 74, 3675; d) R. Zhang, J. Liu, S. Wang, J. Niu, C. Xia, W. Sun, ChemCatChem 2011, 3, 146. T. Flessner, S. Doye, J. Prakt. Chem. 1999, 341, 186. For details of reactions between 3,5-dimethylphenol and the four 4-nitrohaloarenes by using LiOH as base see the Supporting Information. Leadbeater et al. reported microwave-enhanced Suzuki reactions catalyzed by sub-ppm amounts of palladium species present in commercial ultrapure sodium carbonate, see: a) N. E. Leadbeater, M. Marco, Angew. Chem. 2003, 115, 1445; Angew. Chem. Int. Ed. 2003, 42, 1407; b) R. K. Arvela, N. E. Leadbeater, M. S. Sangi, V. A. Williams, P. Granados, R. D. Singer, J. Org. Chem. 2005, 70, 161. For a recent review on the role of
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[10] [11] [12]
[13]
[14] [15]
[16]
[17]
[18]
[19]
trace metal impurities in catalysis, see: c) I. Thom, A. Nijs, C. Bolm, Chem. Soc. Rev. 2012, 41, 979. For a discussion on this topic, see: d) N. E. Leadbeater, Nat. Chem. 2010, 2, 1007. See the Supporting Information. The remaining 1-iodo-2-nitrobenzene was reduced to nitrobenzene under the reaction conditions. The conversions of the starting 3,5-dimethylphenol are, respective of the aryl halide (following the order I, Br, Cl), 99, 95, and 60 %. The isolated yields, following the same order, are 70, 64, and 40 %. Complete selectivity for the formation of diaryl ether 12 was observed. The reactions were carried out in duplicate, the conversions varying by 1 %. a) J. D. Loudon, N. Shulman, J. Chem. Soc. 1941, 722; b) J. F. Bunnett, E. W. Garbisch, K. M. Pruitt, J. Am. Chem. Soc. 1957, 79, 385; c) H. Suhr, Chem. Ber. 1964, 97, 3268. R. W. Taft, F. Anvia, M. Taagepera, J. Cataln, J. Elguero, J. Am. Chem. Soc. 1986, 108, 3237. For optimization details of the reaction between 3,5-dimethylphenol and 4-iodobenzonitrile at various temperatures see the Supporting Information. For some precedents by our group on the copper-catalyzed arylation of O-nucleophiles, see: a) H.-J. Cristau, P. Cellier, J.-F. Spindler, M. Taillefer, Org. Lett. 2004, 6, 913; b) A. Ouali, J.-F. Spindler, A. Jutand, M. Taillefer, Organometallics 2007, 26, 65; c) A. Tlili, F. Monnier, M. Taillefer, Chem. Eur. J. 2010, 16, 12299. Note that 2,2,6,6-tetramethylheptanedione was purified by column chromatography and distillation prior to use. Reactions were set up using the b-diketone purchased from Sigma–Aldrich, Alfa Aesar, and Acros. Additionally, the b-diketone was synthesized by using known procedures. a) P.-F. Larsson, A. Correia, M. Carril, P.-O. Norrby, C. Bolm, Angew. Chem. 2009, 121, 5801; Angew. Chem. Int. Ed. 2009, 48, 5691; b) E. Zuidema, C. Bolm, Chem. Eur. J. 2010, 16, 4181; c) P.-F. Larsson, C. Bolm, P.-O. Norrby, Chem. Eur. J. 2010, 16, 13613; For ligand-accelerated catalysis, see: d) D. J. Berrisford, C. Bolm, K. B. Sharpless, Angew. Chem. 1995, 107, 1159; Angew. Chem. Int. Ed. Engl. 1995, 34, 1059. Y. Yuan, I. Thom, S. H. Kim, D. Chen, A. Beyer, J. Bonnamour, E. Zuidema, S. Chang, C. Bolm, Adv. Synth. Catal. 2010, 352, 2892.
Received: February 24, 2014 Published online on April 15, 2014
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Communication
& Synthetic Methods
On the Frontier Between Nucleophilic Aromatic Substitution and Catalysis Martin Pichette Drapeau,[a, b] Thierry Ollevier,*[a] and Marc Taillefer*[b] Abstract: A study on the arylation of heteroatom nucleophiles by using activated haloarenes, with or without metal catalysts, is reported. A discussion concerning the involvement of traces of metals is presented, supported by an unexpected ''ligand'' effect in the absence of added metal catalysts. We believe that the frontier between nucleophilic aromatic substitution and catalysis will likely prove to be much harder to delimit than is generally thought.
Nucleophilic aromatic substitution (SNAr) reactions of aryl halides, allowing for the formation of C(aryl) heteroatom bonds, have been known since the 19th century.[1] Depending on the reaction conditions, several mechanisms can be considered for this transformation. The most important of these mechanisms is classical addition–elimination (SNAr mechanism), in which halogens ortho or para to strong electron-withdrawing groups are substituted by heteroatom nucleophiles through Meisenheimer–Jackson complexes.[2] There is an abundance of literature reports on the reactions of O- and N-nucleophiles with aryl halides (F, Cl, or Br), activated by electron-withdrawing groups, that require classical or microwave heating, or sonochemical conditions.[3] In particular, the nitro functionality acts as a highly activating group in SNAr because of its excellent ability to stabilize reaction intermediates through resonance structures. Another widely used method for C(aryl) heteroatom bond formation requires the presence of transition-metal catalysts for the coupling of nucleophiles with non-activated and activated aryl halides.[4] Thus, electron-deficient aryl iodides, bromides, chlorides, and even fluorides have been used in various metal-catalyzed protocols. However, the latter two reagents in particular are excellent substrates for SNAr reac-
tions. From a purely theoretical point of view, one could question the necessity of added metals in some of the corresponding systems. In the same manner, even for activated aryl iodides, which are among the worst substrates for SNAr reactions, some rare examples of coupling with nucleophiles in metal-free conditions have been reported. These examples make use of highly activated 1-iodo-4-nitrobenzene, under either microwave/sonochemical[5] or thermal conditions,[6] as well as 4-iodobenzonitrile and 4-iodoacetophenone, as reported previously by our group.[6b] Herein, we wish to disclose our study on reactions of electron-deficient aryl halides with aromatic heteroatom (O- and N-) nucleophiles, from which unexpected results were obtained. Taking into account the few previous literature reports on SNAr reactions of phenols with 1-iodo-4-nitrobenzene,[6] the reaction of the latter with 3,5-dimethylphenol was first revisited. Indeed, nucleophilic aromatic substitution involving electronpoor aryl iodides, even when substituted by the strongly activating NO2 group, is not really expected. In our first test, which was a control experiment in the absence of a base, no reaction occurred at 90 8C in DMF, a classical solvent for SNAr (Table 1, entry 1). However, under these conditions, the desired diaryl ether 1 was quantitatively formed
[a] M. Pichette Drapeau, Prof. Dr. T. Ollevier Dpartement de Chimie Pavillon Alexandre-Vachon, Universit Laval 1045, avenue de la Mdecine, Qubec (Qc), G1V 0A6 (Canada) E-mail: [email protected] [b] M. Pichette Drapeau, Dr. M. Taillefer CNRS, UMR 5253, AM2N Institut Charles Gerhardt Montpellier ENSCM 8, rue de l’cole Normale, F-34296 Montpellier Cedex 5 (France) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304164 and includes general procedures for isolation and full characterization of every product, as well as optimization tables. Chem. Eur. J. 2014, 20, 5231 – 5236
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Table 1. Reaction of 3,5-dimethylphenol with 1-iodo-4-nitrobenzene.[a]
1 2 3 4 5 6 7 8 9 10 11 12
Base (purity %)[b]
Solvent
Yield 1 [%][c]
Absence Cs2CO3 (99.995) K3PO4 (97) K2CO3 (97) LiOtBu (99.9) LiOH (99.995) NaOH (99.99) CsOH (99.95) Pyridine (98) Cs2CO3 (99.995) Cs2CO3 (99.995) Cs2CO3 (99.995)
DMF DMF DMF DMF DMF DMF DMF DMF DMF toluene MeCN DMSO
0 100[d,e] 99 68 55 93 76 83 0 0 30 85
[a] Conditions: 3,5-Dimethylphenol (1.0 equiv), 1-iodo-4-nitrobenzene (1.5 equiv), base (2.5 equiv), solvent (0.25 m). [b] As determined by the supplier. [c] Yield calculated by 1H NMR spectroscopy by using 1,3,5-trimethoxybenzene as an internal standard. [d] 98 % isolated yield. [e] 61 % yield was calculated by using an equimolar ratio of phenol and aryl iodide.
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication by the addition of Cs2CO3 ; changing the base to K3PO4 also gave an almost complete conversion (Table 1, entries 2 and 3).[7] On the other hand, using K2CO3 led to a good yield and LiOtBu gave only fair results (Table 1, entries 4 and 5). Hydroxide bases were then tested, LiOH resulted in a better conversion than that of both NaOH and CsOH (Table 1, entry 6 versus entries 7 and 8).[8] No reaction occurred when an organic base (pyridine) was used or when the reaction was conducted in toluene, the starting material being quantitatively recovered in both cases (Table 1, entries 9 and 10). A low yield was obtained when the reaction was performed in acetonitrile under reflux, whereas on changing the solvent to DMSO a good yield was achieved (Table 1, entries 11 and 12). Cs2CO3 was chosen for further exemplification studies to allow a comparison of our results with those in the literature. Indeed, Cs2CO3 (in association with DMF) is very frequently used in related metal-catalyzed C O coupling reactions. Although these results seem to confirm preliminary reports on SNAr reactions of 1-iodo-4-nitrobenzene,[6] we controlled the purity of the reagents to detect the possibility of catalysis by trace metal contaminants.[9] Cs2CO3 was purchased from Sigma–Aldrich (99.995 % trace metals basis) and Alfa Aesar (99.994 % trace metals basis). For the latter, a certificate of analysis was available and indicated that metals known to catalyze such reactions (mainly palladium, copper, and rhodium) were not detected in measurable amounts by inductively coupled plasma (ICP) analysis.[10] In addition, both reaction partners (3,5-dimethylphenol and 1-iodo-4-nitrobenzene) were carefully purified by column chromatography, and reactions were conducted in new glassware by using magnetic stirrers treated with aqua regia (nitro-hydrochloric acid) prior to use. Even with these precautions, the reactivity remained essentially the same for each individual reaction. Next, we attempted to extend the scope of this method to various phenols and activated aryl iodides. It is noteworthy that except one previous report,[6b] aryl iodides with a substituent other than NO2 have never been used in SNAr reactions. For each type of substituted aryl iodide, a comparison of its reactivity with the corresponding bromide and chloride was also undertaken to verify the expected order of reactivity of aryl halides; I < Br Cl according to the literature. Because of the high reactivity of nitro-substituted aryl halides, reactions of these substrates were carried out at room temperature. We first observed that the reaction of 1-iodo-4-nitrobenzene with 3,5-dimethylphenol proceeded to completion at room temperature, although the reaction time was very long (Table 2, entry 1). As previously observed, increasing the temperature to 90 8C greatly reduced the required reaction time (Table 2, entry 1’). Reactions of 3,5-dimethylphenol with 1-bromo-, 1-chloro-, and 1-fluoro-4-nitrobenzene also furnished 1 in excellent yields at room temperature and in acceptable reaction times for 1-chloro, and 1-fluoro-4-nitrobenzene (Table 2, entries 2–4). Furthermore, the order of reactivity of the four aryl halides is in good agreement with the literature for SNAr reactions. The reactions of phenol and 4-fluorophenol with 1-iodo4-nitrobenzene under similar conditions also provided diaryl ethers 2 and 3 (Table 2, entries 5 and 6) in quantitative yields. Chem. Eur. J. 2014, 20, 5231 – 5236
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For these two entries, conducting the reactions at 90 8C also greatly reduced the required reaction times (Table 2, entries 5’ and 6’). On using 1-iodo-2-nitrobenzene, a satisfying yield of 4 was obtained at 90 8C (Table 2, entry 7).[11] Importantly, no trace of the desired product was detected on reaction of 1-iodo-3nitrobenzene with 3,5-dimethylphenol at this temperature, demonstrating that an appropriate substitution pattern (ortho and para versus meta), typical of addition–elimination SNAr reactions of aryl halides, is crucial for the reaction to proceed. In addition, aryl halides substituted by the cyano group were also tested. The reactions of 3,5-dimethylphenol with 4-iodo-, 4-bromo-, and 4-chlorobenzonitrile furnished diaryl ether 5 in good yields at 120 8C (Table 2, entries 8–10). The difference in reactivity between the aryl halides was clearly highlighted when the temperature was lowered to 90 8C; 4-iodobenzonitrile gave a significantly lower conversion than 4-bromo- and 4-chlorobenzonitrile (Table 2, entries 8’–10’). Phenols substituted by various electron-withdrawing and electrondonating groups could be coupled with 4-iodobenzonitrile to give diaryl ethers 6–9 in yields ranging from 53 to 97 %, demonstrating the generality of this method (Table 3, entries 11– 14). Moreover, when 2-iodobenzonitrile was used, an excellent 97 % yield of diaryl ether 10 was obtained (Table 2, entry 15). The reactions of 4-haloacetophenones with 3,5-dimethylphenol were also investigated. It was observed that an elevated temperature (145 8C) is necessary to furnish the desired diaryl ether 11 in moderate to excellent yields (Table 2, entries 16– 18). When the reactions were repeated, at 120 8C, with the three aryl halides, the best conversion was obtained in the case of 4-bromoacetophenone, whereas 4-iodo- and 4-chloroacetophenone gave modest results (Table 2, entries 16’–18’). The trifluoromethyl group, a weak electron-withdrawing group, was also tested. The reactions of 4-halobenzotrifluorides with 3,5-dimethylphenol gave the corresponding product 12 in yields ranging from 60 to 91 % at a surprisingly “low” temperature (145 8C), despite the weak activation from the trifluoromethyl group (Table 2, entries 19–21). Even more surprising was the fact that the relative reactivity of the aryl halides decreased in the order I Br > Cl,[12] which is not in perfect agreement with the literature.[1, 13] Moreover, the tendency was the same when the reactions were conducted at 120 8C (Table 2, entries 19’–21’). Finally, a 65 % yield of diaryl ether 13 was obtained by the reaction of 3,5-dimethylphenol with 2-iodobenzotrifluoride (Table 2, entry 22). It is noteworthy that we never observed reduction products of the aryl iodides under these conditions, with the exception of the reaction using 1-iodo-2nitrobenzene. This methodology was next extended to nitrogen nucleophiles (Table 3). We tested the reactivity of azoles, with pyrazole being chosen as the model substrate. The reaction of pyrazole with 1-iodo-4-nitrobenzene at 120 8C provided N-aryl azole 14 in excellent yield (Table 3, entry 1). It was also possible to generate product 15 in very good yields from the corresponding 4-halobenzonitriles at 145 8C (Table 3, entries 2–4), and product 16 in fair to good yields by using 4-halobenzotrifluorides (Table 3, entries 5–7). For the latter, 4-chlorobenzotrifluoride again proved to be less reactive than its iodo- and
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Communication Table 2. Synthesis of diaryl ethers 1–13.[a]
R1
X, R2
Diaryl ether
T [oC], t [h]
Yield [%][b]
22, 240 90, 18 22, 80 22, 40 22, 6
95 100 96 98 99
1 1’ 2 3 4
m, m’ (CH3)2
5 5’
H
I, p-NO2
22, 240 90, 18
97 (95) 98
6 6’
p-F
I, p-NO2
22, 240 90, 18
98 (96) 99
7
m, m’ (CH3)2
I, o-NO2
90, 18
62 (60)
120, 24 90, 24 120, 24 90, 24 120, 24 90, 24
83 (76) 50 81 (75) 93 80 (72) 85
I, p-NO2 Br, p-NO2 Cl, p-NO2 F, p-NO2
(93) (98) (92) (96) (98)
8 8’ 9 9’ 10 10’
m, m’ (CH3)2
11
H
I, p-CN
120, 24
84 (81)
12
p-F
I, p-CN
120, 24
95 (92)
13
p-OMe
I, p-CN
120, 24
97 (93)
14
m, m’ (CF3)2
I, p-CN
120, 24
53 (46)
15
m, m’ (CH3)2
I, o-CN
120, 24
97 (94)
145, 120, 145, 120, 145, 120,
24 24 24 24 24 24
62 (49) 45 90 (71) 75 95 (73) 64
145, 120, 145, 120, 145, 120,
24 24 24 24 24 24
91 (70) 50 83 (64) 45 60 (40) 18
16 16’ 17 17’ 18 18’
I, p-CN Br, p-CN Cl, p-CN
I, p-COMe m, m’ (CH3)2
Br, p-COMe Cl, p-COMe
19 19’ 20 20’ 21 21’
m, m’ (CH3)2
22
m, m’ (CH3)2
I, p-CF3 Br, p-CF3 Cl, p-CF3
I, o-CF3
reflux, 24
83 (65)
[a] Conditions: Phenol (1.0 equiv), aryl halide (1.5 equiv), Cs2CO3 (2.5 equiv), DMF (0.25 m). [b] Yield calculated by 1H NMR spectroscopy by using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are given in parentheses.
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bromo- counterparts, as already observed for the reactions of these substrates with phenols. Conducting the reaction of imidazole or pyrrole with 1-iodo-4nitrobenzene resulted in no conversion of the nucleophile, suggesting that an a-effect[14] is critical for the success of the coupling of azoles with aryl halides (Table 3, entry 8). Indeed, the reaction between 1,2,4-triazole and 1-iodo-4-nitrobenzene furnished N-aryl azole 17 in very good yield (Table 3, entry 9). In the literature, the arylation of phenols or nitrogen heterocycles involving electron-deficient iodo-, bromo-, and sometimes chloroarenes is described, at comparable or lower temperatures than those in our study, by means of transition-metal-catalyzed protocols (mainly involving copper and palladium species). However, the need for a catalyst, or the reaction temperature at which the use of a catalyst is required, is not always evident because the control experiments in the absence of metals are often missing or only concern the simplest category of substrates (halobenzenes). For example, concerning the C O bond formation in the case of halonitroarenes, it is clear from this study (Table 2) that the use of a metal catalyst will rarely be necessary. Indeed, even for iodoarenes, which are among the worst substrates for SNAr reactions, good to excellent yields of diarylethers 1–4 were obtained at a reasonable temperature and reaction time (90 8C, 18 h: Table 2, entries 1’, 5’, 6’, and 7). With the less-activating cyano substituent, the same conclusion may be drawn for the arylation at 90 8C, in the absence of a catalyst, of 3,5-dimethylphenol with bromoand chloroarenes (Table 2, entries 9’ and 10’). As expected, a higher temperature (120 8C) was necessary for the ar-
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication system at this temperature and noticed quantitative coupling between 3,5-dimethylphenol and 4iodoacetophenone (CuI 10 mol %/ TMHD 20 mol %). Importantly, we [b] Azole X, R N-aryl azole T [8C] Yield [%] observed an unexpected effect in the control experiments we per[c] 1 pyrazole I, p-NO2 120 98 (95) formed during this study. Indeed, in the presence of the b-diketone 2 I, p-CN 145 88 (85) 3 Br, p-CN 145 92 (86) pyrazole (TMHD), without copper,[17] the 4 Cl, p-CN 145 93 (90) conversion of 3,5-dimethylphenol into diaryl ether 11 was increased 5 I, p-CF3 145 84 (75) from 45 to 65 and 92 % with 0, 6 Br, p-CF3 145 81 (72) pyrazole 0.2, and 2 equivalents of TMHD, 145 59 (43) 7 Cl, p-CF3 respectively, in otherwise un145 0 8 imidazole I, p-NO2 changed conditions (Table 4, entries 1–3). For 4-bromoacetophe[c] 120 86 (83) 9 1,2,4-triazole I, p-NO2 none, a similar enhancement of conversion into diaryl ether 11 [a] Conditions: Azole (1.0 equiv), aryl iodide (1.5 equiv), Cs2CO3 (2.5 equiv), DMF (0.25 m). [b] Yield calculated by 1 was observed. Addition of only H NMR spectroscopy by using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are given in pa0.2 equivalents of TMHD inrentheses. [c] 18 h. creased the conversion from 75 to 100 % (Table 4, entries 4 and 5). On the contrary, addition of 0.2 equivalents of TMHD did ylation, in excellent yields, of various phenols with iodobenzonot have any effect on the coupling reaction of 4-chloroacetonitriles (Table 2, entries 8, 11–15). However, if the use of phenone (Table 4, entries 6 and 7). a metal catalyst is not necessary in these cases, it is essential Concerning substrates with a trifluoromethyl substituent, when working at lower temperatures. For example, no trace of the yields of coupling products are good when the reaction is diaryl ether 5 was obtained by reacting 3,5-dimethylphenol carried out at 145 8C, but disappointing at 120 8C (Table 2, enwith 4-iodobenzonitrile at 50 8C (compared with 83 % yield at tries 19–21’). Noticeably, no similar positive effect was ob120 8C).[15] On the other hand, conducting the reaction at 50 8C served when the b-diketone alone was added to the reaction in the presence of CuI (0.5 mol %) and 2,2,6,6-tetramethylhepof 3,5-dimethylphenol and 4-iodobenzotrifluoride at these eletanedione (1 mol %, TMHD) provided a very low (5 %) yield of vated temperatures. the desired diaryl ether, 5, (Scheme 1).[16] With a higher loading On the basis of our general results, one could consider, in of the copper catalyst (10 mol %) and ligand (20 mol %), a quansome cases, that trace metals are involved in the reactions pretitative yield was obtained. sented in this article.[9] For the C O bond formation (Table 2), this suggestion would provide an explanation for the reaction of 3,5-dimethylphenol with 4-iodobenzotrifluoride invariably proceeding with better conversion (and yield) than the reaction of 3,5-dimethylphenol with 4chlorobenzotrifluoride (Table 2, Scheme 1. Reaction of 3,5-dimethylphenol with 4-iodobenzonitrile: A comparative study. Conditions: 3,5-Dimecompare entries 19 and 19’ with thylphenol (1.0 equiv), 4-iodobenzonitrile (1.5 equiv), Cs2CO3 (2.5 equiv), DMF (0.25 m). 21 and 21’); iodine is a better leaving group in metal-catalyzed Thus, two mechanistic pathways seemingly compete. The coupling reactions. Indeed, one could imagine that catalysis choice of metal-catalyzed or SNAr conditions depends on the plays a more important role than SNAr when the electron-withtemperature threshold tolerated by the substituents and on drawing group is not sufficiently strong (CF3 or MeCO versus the eventual interest to avoid metal traces, for example in the NO2, for example). For the C N bond formation (Table 3), the synthesis of molecules of pharmaceutical interest. same hypothesis can be proposed for the reactions of pyraWith the acetyl substituent, the presence of a catalyst is not zoles at 145 8C; 4-iodobenzotrifluoride reacts more smoothly necessary at 145 8C (Table 2, entries 16–18). At 120 8C, the yield than 4-chlorobenzotrifluoride (Table 3, entries 5 and 7). For the of coupling product is particularly low for the iodo derivative results presented in Table 4, a similar argument could be ap(Table 2, entry 16’). We tested a classical copper catalytic plied. Thus, in reactions of iodo- and bromo-substituted acetoTable 3. Synthesis of N-aryl azoles 14–17.[a]
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Communication Table 4. The effect of the addition of 2,2,6,6-tetramethylheptanedione on the arylation of 3,5-dimethylphenol with 4-haloacetophenones without added copper catalysts.[a]
1 2 3 4 5 6 7
X
TMHD [equiv]
Conversion to 11 [%][b]
I I I Br Br Cl Cl
– 0.2 2 – 0.2 – 0.2
45 65[c] 92 75 100 65 64
[a] Conditions: 3,5-Dimethylphenol (1.0 equiv), 4-haloacetophenone (1.5 equiv), Cs2CO3 (2.5 equiv), DMF (0.25 m). [b] 1H NMR conversion based on phenol by using 1,3,5-trimethoxybenzene as an internal standard. [c] Quantitative yield achieved by adding 10 mol % of CuI.
phenones, the addition of the b-diketone could enhance the reactivity of transition metals that may already be present in the reaction mixture. The fact that the reactivity of 4-chloroacetophenone was unchanged by the addition of a ligand suggests that, in this case, nucleophilic aromatic substitution alone explains phenol arylation. Such an effect has been disclosed for copper-catalyzed arylation of nucleophiles with iodoarenes by using N,N’-dimethylethylenediamine (DMEDA).[18] The presence of the diamine ligand is thought to increase the potency of the catalyst, which is present in part-per-million loadings. Interestingly, the ligand-to-metal ratio needs to be very high, otherwise no coupling takes place. In our case, the use of DMEDA did not provide any enhancement to the reactions described in Table 4. Trace amounts of transition metals, which could have an effect on the reaction outcome when the b-diketone is added, may ultimately be provided by any of the reagents used in the arylations. However, the presence of trace metals would be rather surprising, considering that the phenols, aryl halides, 2,2,6,6-tetramethylheptanedione, and DMF were extensively purified before the reactions, and cesium carbonate was obtained in the highest purity (99.995 %) commercially available. Moreover, some of our results do not support the intervention of metal catalysis. For example, the absence of any “ligand” effect (without copper) on the coupling of 4-iodobenzotrifluoride is not in accordance with this hypothesis. The same applies for the coupling of 3,5-dimethylphenol with 4-iodoacetophenone in the presence of 20 mol % of TMHD. In this case, a 65 % yield of coupling product is obtained, whereas a quantitative yield is obtained by using 4-bromoacetophenone (Table 4, entries 2 and 7). Metal catalysis should arguably favor the reaction of the iodoarene, or at least give comparable yields to the reaction of the bromoarene. However, it seems unlikely that the b-diketone can alone promote coupling reactions between phenols and aryl halides. It is worth noting that these reactions could eventually proceed via aryne intermediates (benzyne mechanism); however, Chem. Eur. J. 2014, 20, 5231 – 5236
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strong bases are traditionally required for this type of SNAr reaction, generally providing a mixture of regioisomers. However, we never experienced selectivity problems, even at elevated temperatures.[19] Concerning the possibility of free-radical SNAr mechanisms (SRN1), radical scavengers 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO), galvinoxyl, and acrylonitrile failed to inhibit the reactions shown in Table 2, suggesting that radicals are not involved. In summary, we have reported conditions for reactions of aromatic heteroatom nucleophiles with electron-deficient aryl halides without the need for added transition-metal salts. It appears from this study that before using metal catalysts, control experiments in the absence of metal catalysts are necessary for every activated aryl halide, including iodides. Incidentally, these control experiments are often missing in the literature or concern the simplest category of substrates (halobenzenes). The choice between SNAr and catalysis would then depend on the temperature threshold tolerated by the substrates and on the eventual interest to avoid metal traces, for example in the synthesis of molecules of pharmaceutical interest. We do not have clear hypotheses for the possible reaction pathways. With regard to the great care with which we undertook this study, it would seem unwise to affirm that the reactions of activated iodo- and bromoarenes described herein are catalyzed by trace amounts of transition metals. However, some results, which include the unexpected “ligand” effect observed for the arylation of 3,5-dimethylphenol with 4-iodo and 4-bromoacetophenone, support this theory. Theoretically determining the frontier between nucleophilic aromatic substitution and catalysis will likely prove to be much harder than is generally thought.
Acknowledgements This work was financially supported by Natural Sciences and Engineering Research Council of Canada (NSERC), Fonds de recherche du Qubec–Nature et Technologies (FRQNT), Conseil Franco-Qubcois de Coopration Universitaire (CFQCU), Centre in Green Chemistry and Catalysis (CGCC), Universit Laval, Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche (ANR), and Ecole Nationale Suprieure de Chimie de Montpellier (ENSCM). M.P.D. thanks FRQNT for a doctoral scholarship and an international internship grant, as well as CGCC for a complementary doctoral scholarship. Keywords: aryl halides · catalysis · diaryl ether · nucleophilic aromatic substitution · transition metals
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Received: February 24, 2014 Published online on April 15, 2014
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